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Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits
1Infectious Diseases Laboratory, San Francisco General Hospital, University of California, San Francisco, USA.
Abstract:
Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.
Insights
Newer quinolones show improved bactericidal activity in cerebrospinal fluid (CSF) for treating pneumococcal meningitis. Their effectiveness in CSF correlates with concentration relative to the minimum bactericidal concentration (MBC).
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Pneumococcal meningitis remains a significant health concern requiring effective antibiotic treatment.
- Cerebrospinal fluid (CSF) penetration and bactericidal activity are critical for antibiotics targeting meningitis.
Purpose of the Study:
- To compare the pharmacokinetics and bactericidal activities of older and newer quinolones against ceftriaxone in a rabbit model of pneumococcal meningitis.
- To evaluate the relationship between antibiotic concentration in CSF and bactericidal efficacy.
Main Methods:
- A rabbit model of Streptococcus pneumoniae meningitis was used.
- Pharmacokinetics and bactericidal activity in CSF were assessed for ciprofloxacin, ofloxacin, levofloxacin, temafloxacin, CP-116,517, Win 57273, and ceftriaxone.
- Correlation between CSF concentrations, minimum bactericidal concentrations (MBCs), and bactericidal rates was analyzed.
Main Results:
- All tested quinolones demonstrated better CSF penetration than ceftriaxone, with entry rates linked to lipophilicity.
- Newer quinolones (CP-116,517, Win 57273) exhibited significantly enhanced bactericidal activity in CSF compared to older quinolones.
- Bactericidal activity in CSF was rapid when the ratio of CSF concentration to MBC exceeded 10 for all antibiotics.
Conclusions:
- Newer quinolones with improved in vitro activity show comparable in vivo bactericidal efficacy to ceftriaxone in experimental pneumococcal meningitis.
- Optimizing CSF antibiotic concentrations relative to MBC is crucial for achieving rapid bactericidal effects.